Emerging Insights Into the Molecular and Cellular Basis of Glioblastoma
Total Page：16
File Type：pdf, Size：1020Kb
Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Emerging insights into the molecular and cellular basis of glioblastoma Gavin P. Dunn,1,2,3 Mikael L. Rinne,2,3,4 Jill Wykosky,5 Giannicola Genovese,2 Steven N. Quayle,2 Ian F. Dunn,6 Pankaj K. Agarwalla,1,2,3 Milan G. Chheda,2,3,7 Benito Campos,8 Alan Wang,9 Cameron Brennan,10 Keith L. Ligon,11 Frank Furnari,5,12 Webster K. Cavenee,5 Ronald A. Depinho,9 Lynda Chin,13 and William C. Hahn2,3,14 1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA; 2Department of Medical Oncology, Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; 3Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; 4Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; 5Ludwig Institute for Cancer Research, University of California at San Diego School of Medicine, La Jolla, California 92093-0660, USA; 6Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; 7Department of Neurology, the Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 8Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany; 9Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 10Department of Neurosurgery, the Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; 11Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; 12Department of Pathology, University of California at San Diego, La Jolla, California 92093-0660, USA; 13Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Glioblastoma is both the most common and lethal pri- and temozolomide therapy. Unfortunately, current stan- mary malignant brain tumor. Extensive multiplatform dard-of-care therapy results in a median survival of only genomic characterization has provided a higher-resolu- 12–15 mo (Stupp et al. 2005). tion picture of the molecular alterations underlying this The emergence of a molecularly focused approach to disease. These studies provide the emerging view that cancers represents a profound shift in our approach to the ‘‘glioblastoma’’ represents several histologically similar diagnosis and treatment of malignancy. This framework yet molecularly heterogeneous diseases, which influ- centers on a new taxonomy that describes cancers by ences taxonomic classification systems, prognosis, and their molecular alterations and the identification of in- therapeutic decisions. hibitors that target these cancer-specific changes. In- deed, therapies targeting HER2-amplified breast cancer (Slamon et al. 2001), CML harboring the BCR–ABL In his effort in the 1920s to cure two comatose patients translocation (Druker et al. 2001), mutant EGFR lung with extensive glioblastomas, neurosurgeon Walter Dandy took the radical step of removing the entire affected cancer (Lynch et al. 2004), lung cancer harboring the hemisphere in each of these patients. Despite these heroic EML4–ALK translocation (Kwak et al. 2010), and BRAF interventions, both of these patients succumbed to their mutant melanoma (Chapman et al. 2011) provide clear disease due to involvement of the contralateral hemisphere proof of principle for this approach. Histopathologic (Dandy 1928). More than 80 years later, we continue to face diagnosis is increasingly being supplemented with annota- the same clinical challenges illustrated by this vignette tion of amplification or mutational status where relevant from the early 20th Century. Glioblastoma represents the (MacConaill et al. 2009; Dias-Santagata et al. 2010), and most common primary intrinsic malignant brain tumor these data subsequently inform therapeutic decision-mak- diagnosed each year in the United States; there are ;10,000 ing, all in a time frame from target discovery to therapy new diagnoses annually, and >50,000 patients are currently that is becoming progressively shorter (Chabner 2011). living with the disease (Davis et al. 2001; Porter et al. 2010; However, despite clinical progress across many cancer CBTRUS 2011). The clinical hallmarks of glioblastoma are types and extensive characterization of genomic alter- its aggressive growth and inexorable recurrence despite ations in glioblastoma, we still have not identified and multimodal therapy with surgery followed by radiation exploited clinically meaningful tumor dependencies in this dreaded disease. [Keywords: glioblastoma; invasion; angiogenesis; tumor-initiating cells; The recent characterization of the genome (Beroukhim IDH1; glioma classification] et al. 2007; The Cancer Genome Atlas Research Network 14Corresponding author. E-mail [email protected]. 2008; Parsons et al. 2008) and transcriptome (Phillips et al. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.187922.112. 2006; Verhaak et al. 2010) of glioblastoma provides a high- 756 GENES & DEVELOPMENT 26:756–784 Ó 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Molecular and cellular basis of glioblastoma resolution picture of the glioblastoma landscape that has chromosomes as well as focal events involving one or revealed the major structural and expression alterations a few genes. The development of high-resolution, array- that may drive disease pathogenesis and biology. These based comparative genomic hybridization (CGH) using comprehensive data sets reveal ‘‘glioblastoma’’ as a het- bacterial artificial chromosomes, oligomers, and single- erogeneous collection of distinct diseases with multiple nucleotide polymorphism (SNP) arrays made possible dependencies both within and across each particular sub- the systematic analysis of cancer genomes and defined type. Here we summarize recent efforts to catalog the many new recurrent SCNAs in cancer (Chin et al. 2011). structural genomic landscape of glioblastoma and focus on To fully explore these data, several groups have also emerging insights into critical molecular pathways cen- developed bioinformatic tools to highlight the cancer- tral to glioblastoma pathobiology. derived genomic alteration signals from among the back- ground noise (Beroukhim et al. 2007; Greenman et al. 2007; Wiedemeyer et al. 2008; Riddick and Fine 2011). Current histopathological classification These methodologies, including Genomic Identification of Significant Targets in Cancer (GISTIC) (Beroukhim et al. As described by the World Health Organization (WHO) 2007; Mermel et al. 2011) and Genomic Topography Scan classification (Louis et al. 2007), malignant diffuse glio- (GTS) (Wiedemeyer et al. 2008), were first deployed in mas are comprised of astrocytic, oligodengroglial, and glioblastoma and subsequently across thousands of cancer mixed oligoastrocytic neoplasms based solely on mor- samples (Beroukhim et al. 2010; http://www.broadinstitute. phology and are further subdivided by tumor grade based org/tumorscape). Combined work using these tools and on additional histologic features present in the tumor. others (Bredel et al. 2005; Kotliarov et al. 2006) identified Nuclear atypia and mitotic activity are required criteria overlapping presumed targets of amplification (including for grade III lesions, and the presence of necrosis or EGFR, MET, PDGFRA, MDM4, MDM2, CCND2, PIK3CA, microvascular proliferation is required for the diagnosis MYC, CDK4,andCDK6) and deletion (including CDKN2A/ of grade IV astrocytoma, glioblastoma (Miller and Perry B, CDKN2C, PTEN,andRB1) in glioblastoma. 2007). While 90%–95% of glioblastomas arise de novo This work in SCNAs preceded two recent studies that and are considered ‘‘primary,’’ ;5%–10% arise from lower- further clarified our understanding of the glioblastoma grade gliomas in younger patients and are termed ‘‘sec- genomic landscape (The Cancer Genome Atlas Research ondary’’ (Biernat et al. 2004; Ohgaki and Kleihues 2005). Network 2008; Parsons et al. 2008). The Cancer Genome Together with grade III anaplastic astrocytoma, which has Atlas (TCGA) pilot project, the first of many ongoing an incidence of >1500 cases annually (CBTRUS 2011), comprehensive TCGA consortium-based cancer genome these tumors comprise the clinical entity termed ‘‘ma- analyses (http://cancergenome.nih.gov), applied multiplat- lignant glioma.’’ However, as discussed below, emerging form profiling to systematically and comprehensively define classification schemes are likely to incorporate molecular the genomic landscape of glioblastoma. This approach used differences that distinguish these tumors (von Deimling targeted Sanger sequencing to investigate 601 genes in 91 et al. 2011). samples as well as array-based platforms to analyze copy number, mRNA expression, and the epigenetic state of Large-scale genomic studies of glial neoplasms ;200 tumors, most of which were untreated, primary glioblastomas. This larger effort confirmed prior SCNA Glioblastoma, like other cancers, is the product of accu- analyses on smaller numbers of tumors and also identi- mulated genetic and epigenetic alterations (Vogelstein fied novel lesions,